Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice

Alkaline sphingomyelinase (alk-SMase) hydrolyses sphingomyelin (SM) to ceramide in the gut. To evaluate the physiological importance of the enzyme, we generated alk-SMase knockout (KO) mice by the Cre-recombinase-Locus of X-over P1(Cre-LoxP) system and studied SM digestion. Both wild-type (WT) and KO mice were fed H-3-palmitic acid labeled SM together with milk SM by gavage. The lipids in intestinal content, intestinal tissues, serum, and liver were analyzed by TLC. In KO mice, nondigested H-3-SM in the intestinal content increased by 6-fold and the formation of H-3-ceramide decreased markedly, resulting in 98% reduction of H-3-ceramide/H-3-SM ratio 1 h after gavage. The absorbed H-3-palmitic acid portion was decreased by 95%. After 3 h, a small increase in H-3-ceramide was identified in distal intestine in KO mice. In feces, H-3-SM was increased by 243% and ceramide decreased by 74% in the KO mice. The KO mice also showed significantly decreased radioactivity in liver and serum. Furthermore, alkaline phosphatase activity in the mucosa was reduced by 50% and histological comparison of two female littermates preliminarily suggested mucosal hypertrophy in KO mice.jlr This study provides definite proof for crucial roles of alk-SMase in SM digestion and points to possible roles in regulating mucosal growth and alkaline phosphatase function.-Zhang, Y., Y. Cheng, G. H. Hansen, L-L. Niels-Christiansen, F. Koentgen, L. Ohlsson, A. Nilsson, and R-D. Duan. Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice. J. Lipid Res. 2011. 52: 771-781.